Diagnosis Of Hereditary Hemochromatosis Research Articles

Value of liver biopsy in the diagnosis of hereditary hemochromatosis

The paper gives an update on the pathogenesis and main clinical manifestations of primary (hereditary) hemochromatosis and its diagnostic methods. It emphasizes the importance of genetic research in the diagnosis of the disease. Its clinical manifestations are associated with iron deposition in organs, such as the liver, pancreas, joints, skin, and heart. The paper points out the importance of liver biopsy using Perls' reaction for the diagnosis of liver damage with the development of fibrosis, cirrhosis, and cancer as the main cause of death in patients with hereditary hemochromatosis and presents the results of examining liver biopsy specimens in patients with hemochromatosis.

Using iron studies to predict HFE mutations in New Zealand: implications for laboratory testing.

The diagnosis of hereditary haemochromatosis (HH) is not straightforward because symptoms are often absent or non-specific. Biochemical markers of iron-overloading may be affected by other conditions. To measure the correlation between iron studies and HFE genotype to inform evidence-based recommendations for laboratory testing in New Zealand. Results from 2388 patients genotyped for C282Y, H63D and S65C in Wellington, New Zealand from 2007 to 2013 were compared with their biochemical phenotype as quantified by serum ferritin (SF), transferrin saturation (TS), serum iron (SI) and serum transferrin (ST). The predictive power of these markers was evaluated by receiver operator characteristic (ROC) curve analysis, and if a statistically significant association for a variable was seen, sensitivity, specificity and predictive values were calculated. Test ordering patterns showed that 62% of HFE genotyping tests were ordered because of an elevated SF alone and only 11% of these had a C-reactive protein test to rule out an acute phase reaction. The association between SF and significant HFE genotypes SF was low. However, TS values ≥45% predicted HH mutations with the highest sensitivity and specificity. A SF of >1000 µg/L was found in one at-risk patient (C282Y homozygote) who had a TS <45%. Our analysis highlights the need for clear guidelines for investigation of hyperferritinaemia and HH in New Zealand. Using our findings, we developed an evidence-based laboratory testing algorithm based on a TS ≥45%, a SF ≥1000 µg/L and/or a family history of HH which identified all C282Y homozygotes in this study.

Identification of New BMP6 Pro-Peptide Mutations in Patients with Unexplained Iron-Overload

▪Background: Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused by mutations in at least 5 different genes (HFE, HJV, TFR2, SLC40A1, and HAMP) involved in the production and function of the liver hormone hepcidin, a key regulator of iron metabolism. Nevertheless, patients with a HH-like phenotype that remains unexplained, despite extensive sequencing of the known genes, are not infrequently seen at referral centres, implicating the role of still unknown genetic factors. A compelling candidate is Bone Morphogenetic Protein 6 (BMP6), a member of TGFb superfamily, whose expression is stimulated by increased iron stores in the liver. BMP6 acts as a major activator of the BMP-SMAD signalling pathway, ultimately leading to the upregulation of hepcidin gene transcription. Indeed, early this year French Authors have described 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with mild to moderate, late onset, unexplained iron overload (Daher R, Gastroenterology 2016).Methods: we recently updated our next generation sequencing (NGS)-based second level genetic test for the molecular diagnosis of non-HFE HH (Badar S, Am J Hematol 2016), by adding a number of novel potential candidate genes, including BMP6, to the panel of the 5 known HH genes. This test was applied to 38 patients evaluated at our tertiary referral centre for iron disorders, because of an unexplained iron overload phenotype.Results: we found 3 heterozygous missense mutations in BMP6 gene in 4 patients with unexplained, late-onset, iron overload, from 3 different families. Their relevant clinical data are summarized into Table 1. Of note, 1 mutation (p.Leu96Pro) was the same recently described by Daher et al. and proven to be functional. The other two mutations (p.Glu112Gln, p.Arg257His) were novel, predicted damaging by bioinformatic tools, and both located in the pro-peptide domain, known to be crucial for appropriate BMP6 processing and secretion. They were further studied by in silico modelling, based on the available 3D structure of the TGFb, which also resulted to be consistent with their pathogenetic role.Conclusions: to the best of our knowledge, our results provide the first independent confirmation of the likely causal role of BMP6 mutations in late onset, moderate iron overload phenotype, unrelated to mutations in the established 5 HH genes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

From the bronze age to the iron age

A 53 year old man, without any previous medical history, presented acutely to the Accident and Emergency Department with a 5 day history of vomiting and abdominal pain on a background of weight loss, fatigue, polyuria and polydipsia for 4 weeks. On examination he was obviously tanned and thin. He was clinically dehydrated and had palpable hepatomegaly. Immediate biochemical testing revealed hyperglycaemia with a venous blood glucose of 20.7 mmol/l, a metabolic acidosis with a pH of 7.1 (and venous bicarbonate of 11.3 mmol/l) and significant ketonuria (++++) thus confirming the clinical suspicion of diabetic keto-acidosis (DKA). His serum ferritin levels were markedly raised at 11346 ug/l with a raised transferrin saturation of 92%. His initial basal pituitary function showed evidence of partial anterior hypopituitarism. This was manifest by hypogonadotrophic hypogonadism with an FSH of <1 IU/l (2?12),LH of <1 IU/l (2?9) and testosterone of 0.5 nmol/l (9?29). He also had evidence of secondary hypothyroidism (TSH 2 mU/l (0.27?4.2) and free T4 9 pmol/l (12?22)) though his cortisol levels were physiological (820 nmol/l at 9 am). He was treated with intravenous fluids and insulin initially and this was later converted to subcutaneous insulin therapy. His HFE gene testing proved positive with him being homozygous for the C282Y mutation thus confirming the diagnosis of Hereditary Haemochromatosis (HH). HH is a disorder of iron metabolism with iron deposits in different organs including within the endocrine system. Although diabetes is a common association of HH, it is unusual for patients to present with DKA. This case serves to highlight this very issue thus serving as a reminder to be aware of potential causes of secondary diabetes when assessing patients with DKA. It also aims to demonstrate the multi-gland nature of the endocrinopathy encountered by patients with HH.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

Anemia with jaundice: An unusual cause

Anemia and jaundice are two important clinical signs in medicine. Occurrence of these two signs together in a patient suggests hemolytic disorders. Hemochromatosis is a disease characterized by hyperpigmentation, arthralgia and diabetes. The disease usually presents in elderly individuals and is rare in menstruating females. We present a case of a young lady with anemia and unexplained jaundice with extensive work-up leading to the diagnosis of hereditary hemochromatosis with megaloblastic anemia. We present the case to highlight the unusual presentation of anemia and jaundice in a case of hemochromatosis.

Improved detection of hereditary haemochromatosis

AimsThere is high prevalence of hereditary haemochromatosis (HH) in North European populations, yet the diagnosis is often delayed or missed in primary care. Primary care physicians frequently request serum ferritin...

Hereditary Hemochromatosis in an Adult Due to H63D Mutation: The Value of Estimating Iron Deposition By MRI T2* and Dissociation Between Serum Ferritin Concentration and Hepatic Iron Overload

Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive intestinal absorption of dietary iron, causing iron overload in different organs, especially the liver. Hemochromatosis may not be recognized until later in life. Patients are usually asymptomatic but may present with a variety of signs and symptoms. These include: hyper-pigmented skin, hepatomegaly, arthralgia, diabetes mellitusand/or heart failure/arrhythmia.The risk of HH related morbidity in HFE compound homozygotes patients (H63D /H63D) is considered rare, we report a male patient with H63D mutation who developed impaired glucose tolerance, and high hepatic enzymes due to significant iron accumulation in the liver as well as Parkinsonian-like syndrome due to iron deposition in the basal ganglia.A 40 year old Qatari male was referred for evaluation of a rise in hemoglobin and hematocrit values with normal MCV, total leucocyte and platelet counts.The patient was asymptomatic with normal vital signs, no depigmentation or hepato-splenomegaly. Hematologic findings included a hemoglobin concentration of Hb 16.5 g/dL, hematocrit 53%, mean corpuscular volume (MCV) 93 fL/red cell, leucocyte count of 7200/ μL and a platelet count of 199000/μL. His serum ferritin was 359 μg/l ( normal values: < 336 μg/l), serum iron: 37 μmol/l ( normal values <28.6μmol/l), fasting transferrin saturation: 64% (normal < 50%).A random glucose 6.5 and 6.4 mmol/L (normal values 5.5mmol/L ), A1C of 5,4 %, normal creatinine and electrolytes, alanine aminotransferase (ALT) of 66 U/l (normal < 40U/l), mild elevation of bilirubin 39 umol/l (normal <24umol/l), normal U&E Hepatitis B and C antibodies were negative.OGTT revealed impaired glucose tolerance. Thyroid function, morning serum cortisol, LH and FSH and serum total testosterone concentrations were in the normal range.A diagnosis of polycythemia vera was excluded on the basis of WHO Criteria 2008. The polymerase chain restriction assay was negative for the common mutation (C282Y) but positive for H63 D mutation.Family screening confirmed HH in his brother (homozygous), whereas his mother, two brothers and the sister were carriers (heterozygous). His four offspring were carriers. This suggested an autosomal recessive mode of inheritance.Conventional MRI study showed a normal liver size with diffuse fatty changes and focal areas of fatty sparing with some evidence of iron deposition. Whereas, T2-star (T2*) sequences showed a diffuse and significant decrease in liver signal intensity. A LIC liver concentration of 27 mg Fe/g dry wt was found (normalvalues:< 2 mg Fe/g dry wt; severe iron overload: ≥15 mg Fe/g dry wt).No significant iron deposition in the spleen, heart or pancreas was observed.At the age of 41 years the patient complained of tremors in both hands and arms while sitting or standing still (resting tremor) that improved with hands movements. A brain MRI revealed iron deposition in the basal ganglion. It was concluded that basal ganglionicn iron deposition mediated the neurological decline.Currently, the transferrin saturation and serum ferritin levels are within normal.Discussion:This is the first case of HH secondary to H63 D among an Arab family and the first reported case of Parkinsonism tremors secondary to this mutation.The H63D HFE variant is less frequently associated with HH, but its role in the neurodegenerative diseases has received a great attention.An accurate evaluation of iron overload is necessary to establish the diagnosis of HH and to guide iron chelation in HH by determination of liver iron concentration (LIC) by means of T2* MRI.Although serum ferritin concentration was only mildly increased a significant siderosis in the liver was detected by MRI T2* technique occurred. Liver siderosis was associated with mild impairment of liver function (increased serum ALT and bilirubin ).Conclusion:Our data further confirm that serum ferritin levels are not an accurate measure of total body iron stores in HH. Iron deposition in the liver and basal ganglion occurred despite mild elevation of ferritin. changes in basal ganglion may present by parkinsonian like tremors in these patients Use,T2* MRI should be encouraged in patients with HH for better evaluation of Iron overload and avoidance of Complications since serum ferritin can be misleading in these conditions. DisclosuresYassin:Qatar National research fund: Patents & Royalties, Research Funding. Aldewik:Qatar Ntional Research Fund: Patents & Royalties, Research Funding.

How do you make the diagnosis of hereditary hemochromatosis (HH)?

How do you make the diagnosis of hereditary hemochromatosis (HH)?

Movement Disorders in Hereditary Hemochromatosis: Case Series

Introduction: Hereditary hemochromatosis (HH) is an autosomal recessive inherited disorder of iron metabolism involving pathological iron deposition in a variety of organs. Movement disorders have been increasingly reported in genetic storage disorders. HH and movement disorders have been sparingly reported. Cellular accumulation of iron is thought to induce lipid peroxydation and results in cell damage and death. Our objective is to review the existing literature about the association of HH and movement disorders. Methods: Extensive review of literature search revealed 13 cases with association of movement disorders in HH. Results: The average age of HH diagnosis is 58 years. The mean age of the beginning of neurological symptoms is 57 years. Conclusion: HH may be clinically asymptomatic, and thus its association with movement disorders is probably underdiagnosed, as illustrated in our small series in which HH was mostly disclosed by routine biochemistry tests. Hence, simple blood analysis, such as serum iron, ferritin, and transferrin saturation levels, should be investigated in any patient with a movement disorder, intellectual deterioration, or both. Phlebotomy is the mainstay of treatment and helps with the other symptoms; its unknown if it can help change the course of neurological disease progression. Therefore, novel treatment methods need to be figured for treating these symptoms. Further studies determining the prevalence of movement disorders in genetically confirmed, iron overloaded HH individuals would clarify association between these 2 conditions. If association becomes apparent between HH and movement disorders, HH should be considered in the evaluation/differential diagnosis of movement disorders patients.Table 1: Movement Disorders and Hereditary Hemochromatosis(HH): Review of Literature

HFE Hemochromatosis: Is there Room to Improve our Diagnosis and Treatment?

Purpose: Hereditary hemochromatosis (HH) is the most common and easily treatable genetic condition amongst Caucasians. Failure to identify and treat HH is associated with significant morbidity and mortality. Herein, we assessed if HH was being diagnosed in a timely manner, and the providers most commonly associated with diagnostic delays. We then evaluated if HH patients were treated to goal ferritin levels of less than 100 ng/ml, as recommended by AASLD. Lastly, we assessed if patients were aware of the need for their offspring to be screened. Methods: This was a retrospective chart review of 23 patients diagnosed with HH at an academic institution between 2000 and 2012. A clinical clue which should lead the astute clinician to consider HH as a diagnosis was defined as abnormal liver function tests or iron studies, family history of HH, or cirrhosis. The time between initial clue appearance and the date an appropriate action was taken on the clue was calculated. A time interval of greater than 90 days was defined as a diagnostic delay. The time between initial clue appearance and diagnosis of HH was calculated. The time to achieve goal ferritin levels was also determined. A telephone interview was conducted to evaluate patient knowledge on the need for their offspring to be screened. Results: C282Y homozygotes represented 16 of the 23 patients. The most common presenting clues were abnormal iron studies (15 patients) and abnormal LFTs (8 patients). A diagnostic delay was found in 10 patients. 18 of the 23 patients had a diagnosis of HH made within 1 year of their presenting clue. PCPs were more commonly involved in diagnostic delays, as compared to gastroenterologists and other sub-specialists. 74% of patients achieved goal ferritin levels of less than 100 ng/ml within 2 years of their diagnosis. Eleven of 12 patients available and eligible for a phone interview were aware of the hereditary nature of the disease and the need for their offspring to be screened. Conclusion: HH is an easily treatable genetic condition; however, without recognition of its presenting clues, timely diagnosis, treatment to recommended ferritin levels, and appropriate screening of offspring of affected patients, the diagnosis may be delayed or missed. There is room to improve our diagnosis of HH, as a diagnostic delay was identified in 43% (10 patients) of our study population. Despite these results, most patients were diagnosed by one year of their presenting clue. Also, most patients were treated to recommended ferritin levels within two years of their diagnosis, and were aware of the need for their offspring to be screened. Further studies are needed to evaluate whether enhancing awareness of HH at the PCP level will decrease diagnostic delays.

Iron storage disease in Asia‐Pacific populations: The importance of non‐HFE mutations

Hereditary hemochromatosis (HH) is a widely recognized and well-studied condition in European populations. This is largely due to the high prevalence of the C282Y mutation of HFE. Although less common than in Europe, HH cases have been reported in the Asia-Pacific region because of mutations in both HFE and non-HFE genes. Mutations in all of the currently known genes implicated in non-HFE HH (hemojuvelin, hepcidin, transferrin receptor 2, and ferroportin) have been reported in patients from the Asia-Pacific region. This review discusses the molecular basis of HH and the genes and mutations known to cause non-HFE HH with particular reference to the Asia-Pacific region. Challenges in the genetic diagnosis of non-HFE HH are also discussed and how new technologies such as next generation sequencing may be informative in the future.

Review and actualizations of Molecular Genetic Diagnosis, Symptoms, and diagnostic strategies of Hereditary Hemochromatosis

The hemochromatosis term describes a group of diseases caused by excess iron in the body. Hemochromatosis is the inborn error of metabolism most frequent (80%) and is considered a potentially serious illness due to cell damage that occur in different organs such as liver, heart, joins, skin or pancreas because for much of the life can develop without symptoms. Hereditary Hemochromatosis (HH) is an autosomal recessive disorder characterized by iron overload. Liver cirrhosis, diabetes, cardiomyopathy, arthritis, hypogonadism and skin pigmentation can be caused by iron overload. Most patients with hemochromatosis are p.Cys282Tyr homozygous or p.Cys282Tyr/p.His63Asp compound heterozygous. In addition to HFE gene, mutations in the genes that encode Hemojuvelin (HJV),Hepcidin (HAMP), Transferring Receptor 2 (TFR2) and Ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this paper is to review the main gene mutations involved in the pathogenesis of HH type 1 to 4 and their genetic testing indication. With diverse diagnostic tests are reporting practices in use, there is a clear need for establishing a review of hemochromatosis genetic testing and diagnostic strategies ofHH. Most importantly, early and effectiveness diagnosis and treatment of HH prevents complications and results in a normal life expectancy. Review of algorithms of diagnostic strategies in HH is presented in this work.

The Hereditary Hyperferritinemia-Cataract Syndrome in 2 Italian Families

Two 8- and 9-year-old brothers were referred to the Pediatric Oncology Unit, Perugia General Hospital, because of hyperferritinemia. Both had a history of bilateral cataract and epilepsy. Genetic investigation revealed two distinct mutations in iron haemostasis genes; homozygosity for the HFE gene H63D mutation in the younger and heterozygosity in the elder. Both displayed heterozygosity for C33T mutation in the ferritin light chain iron response element. A 7-year-old boy from another family was referred to our unit because of hyperferritinemia. Genetic analyses did not reveal HFE gene mutations. Family history showed that his mother was also affected by hyperferritinemia without HFE gene mutations. Magnetic resonance imaging in the mother was positive for iron overload in the spleen. Cataract was diagnosed in mother and child. Further genetic investigation revealed the C29G mutation of the ferritin light chain iron response element. C33T and C29G mutations in the ferritin light chain iron response element underlie the Hereditary Hyperferritinemia-Cataract Syndrome (HHCS). The HFE gene H63D mutation underlies Hereditary Haemochromatosis (HH), which needs treatment to prevent organ damages by iron overload. HHCS was definitively diagnosed in all three children. HHCS is an autosomal dominant disease characterized by increased L-ferritin production. L-Ferritin aggregates accumulate preferentially in the lens, provoking bilateral cataract since childhood, as unique known organ damage. Epilepsy in one case and the spleen iron overload in another could suggest the misleading diagnosis of HH. Consequently, the differential diagnosis between alterations of iron storage system was essential, particularly in children, and required further genetic investigation.

Does hemochromatosis predispose to celiac disease? A study of 29,096 celiac disease patients

Background and aim. Case reports suggest an association between hereditary hemochromatosis (HH) and celiac disease (CD), but estimates of association are lacking. We estimated the association between HH and CD in a population-based study. Material and methods. Case–control study. We identified 29,096 individuals with biopsy-verified CD (equal to villous atrophy, Marsh stage III) through biopsy reports from all 28 pathology departments in Sweden. We then investigated the risk of a clinical diagnosis of HH in CD and in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression was used to calculate odds ratios (ORs) for CD in patients with HH. Results. HH was seen in 30 patients with CD and in 60 matched controls. HH was hence associated with an increased risk of CD (OR = 2.30; 95% CI = 1.53–3.45). Restricting HH to individuals with at least two records of HH, the OR for CD was 2.54 (95% CI = 1.57–4.11), with a similar risk estimate when we only looked at HH diagnosed before CD (and matched date in controls) (OR = 2.64; 95% CI = 1.24–5.60). Conclusion. HH seems to be associated with an increased risk of CD.

An Unusual Case of Hemochromatosis

Purpose: Hereditary Hemochromatosis (HH) is an autosomal recessive disease caused by mutations in the HFE gene on chromosome 6. The frequency of gene mutation averages 7% in north European and American population resulting in 0.5% frequency of homozygotes. Of these, up to 88% develop biochemical evidence of iron overload but only 28% of men and 1% of women will develop clinical symptoms. A 31 year old obese male with past medical history of ADHD who presented for evaluation of chronic mild elevation of liver function tests for the past two years. He complained of severe fatigue, arthralgias and erectile dysfunction for two years. His symptoms appeared to be worsening causing even routine activities difficult. He reported consuming one alcoholic beverage per week. Medication history included amphetamine use for presumed ADHD and flonase inhaler for seasonal allergies. Tylenol or NSAID use was denied. No other medication or drug use was reported by the patient. Vital signs and mental status was normal. Patient was noticed to have a ruddy complexion, a normal cardiopulmonary exam and unremarkable abdominal exam. His testicular size was normal. CBC, BMP and coagulation parameters were normal. LFT's were normal except AST 30-50 IU/L and ALT 60-90 IU/L range. Ultrasound liver showed fatty liver. Hepatitis serologies, ANA, serum alpha-1 antitrypsin, serum ceruloplasmin were normal. Ferritin was found to be elevated at 514 ng/ml. HH gene testing showed two copies of mutation C282Y. Liver biopsy was performed which showed moderate hepatic steatosis and no stainable stores of iron. Endocrinology evaluation revealed hypogonadotropic hypogonadism. Although a majority of C282Y homozygotes may experience biochemically defined abnormalities of iron overload, the penetrance for clinical symptoms, such as cirrhosis, cardiomyopathy, diabetes and arthropathy is low. The diagnosis of HH should not rely on DNA testing alone. Diagnosis of HH should include clinical findings and other test results, such as transferrin, iron saturation and/or serum ferritin studies and/or liver biopsy. In our patient we found no stainable stores of iron in the liver and yet chronic LFT abnormalities, ferritin elevation and hypogonadism were detected. Multiple phelobotimies were done by hematology and normalization of LFT's was achieved. Patient was treated with testosterone replacement for hypogonadotropic hypogonadism. He had marked improvement in symptoms over the next 6 months. This is an unusual case of HH with mild LFT abnormalities, no iron in liver on biopsy and severe endocrine dysfunction. He responded dramatically to phlebotomy both from hepatic and endocrine perspectives.

Hereditary hemochromatosis, the clinician point of view

Hereditary hemochromatosis (HH) is an autosomal recessive disease whose most common form is due to homozygosity for the C282Y mutation of the HFE gene. Its prevalence is estimated between 1/200 and 1/600 in France. This represents potentially several thousands of affected people. The disease is characterized by progressive iron overload, which can lead to irreversible parenchymal tissue damage. When clinical signs become evocative the disease is already at an advanced stage and years of life are probably lost. It is therefore important to detect the disease early. The clinician, either general practitioner or specialist, plays a pivotal role in the diagnostic process: he/she receives complaints of patients, prescribes complementary investigations, conducts the treatment and must organize of the family screening. Based on the French recommendations and on literature data, this paper presents the main lines of management of the patient as responses to the eight following questions: 1) Under what circumstances should the clinician suspect HH? 2) How to conduct investigations in the presence of high ferritin levels? 3) What manifestations must be feared with the worsening of iron overload? 4) What medical evaluation should be performed when the diagnosis of HH has been made? 5) How to conduct iron depletive treatment in practice? 6) How to monitor the treated patient? 7) What is the place of iron-chelating drugs in the treatment of HH? 8) How to take charge of the family members?

A National Survey of Hemochromatosis Patients

Hereditary hemochromatosis (HH) is a common genetic disease in the United States, but little is known about the diagnosis from the patient's perspective. The purpose of this study was to characterize the circumstances surrounding the diagnosis of HH and assess treatments and health information needs. We surveyed US adults aged 18 years and older who were diagnosed with HH after 1996. Response rate was 46%, with a total sample size of 979. Respondents were asked about the use of genetic and clinical markers in their diagnosis, current treatments, and health information needs. Results were stratified by age, education, and income status. Total of 90.0% of women and 75.5% of men were genetically tested for HH (P < .01). Approximately half (52.5%) were diagnosed by a gastroenterologist, hematologist, or other specialty physician and half were diagnosed by a primary care provider. Most of the respondents thought their HH had improved with the initial treatment and most patients were still receiving treatment for HH. Patient interest in learning more about specific hemochromatosis topics was generally high. Since the introduction of genetic identification of HH, these tests have been used in the diagnosis of the majority of patients. Primary care physicians may need to be more aware HH and strategies for diagnosis.

Diagnosis of Hereditary Hemochromatosis in the Era of Genetic Testing

Homozygous C282Y mutation in HFE gene is responsible for the majority of hereditary hemochromatosis cases. Since 1996 this mutation can be identified by a simple genetic test. To determine the clinical presentations in patients with homozygous HFE C282Y mutation and the impact of genetic testing on the time needed for diagnosis. A total of 414 patients diagnosed with C282Y homozygous hereditary hemochromatosis before and after the introduction of genetic testing were evaluated regarding symptoms and clinical findings at diagnosis as well as first hemochromatosis-related clinical features in their past medical history. At the time of diagnosis, the predominant symptom was joint pain, in particular of the hands/wrists. Those patients presenting with hand/wrist arthralgia had significantly higher ferritin levels than patients without this joint involvement (p = 0.0005 for males and p < 0.0001 for females). After the introduction of the HFE genetic test an earlier diagnosis after first onset of hemochromatosis-associated clinical features was observed between 2006 and 2009 vs. 2000-2005 p = 0.01). Arthralgia, in particular of the hands/wrists, is a hallmark of hereditary hemochromatosis and its presence is associated with higher ferritin levels. Despite the availability of a genetic test, it often takes more than 6 years from the first onset of clinical features to diagnose hereditary hemochromatosis. This underlines the importance of raising the awareness of hemochromatosis and its typical clinical presentations.